Familial Mediterranean Fever (FMF) is a rheumatic disease characterized by intermittent fever, serositis and/or synovitis; some patients also develop systemic amyloidosis. FMF is inherited as a single-gene, autosomal recessive disorder. The biochemical lesion of FMF, as well as the chromosomal location of the FMF gene, is unknown. The purpose of this project is to identify the FMF gene by the method of position dependent cloning ("reverse genetics"). During the first year of this project we prepared DNA samples from individuals in a panel of highly informative Israeli FMF families, and used RFLP analysis to exclude the FMF gene from 10% of the genome. Over the last year we have substantially extended this analysis. We have examined, and ruled out, a number of FMF "candidate genes," including serum amyloid A (SAA), interleukins 1, 6, and 8, dopamine beta hydroxylase, several lipocortin genes, and a number of genes encoding structural or regulatory proteins in the complement cascade. We have systematically examined another 100 DNA polymorphisms for possible linkage to the FMF susceptibility gene., and have thereby excluded the FMF gene from more than one third of the genome. Moreover, we have identified a region on the long arm of chromosome 17 where one FMF susceptibility gene may reside, and we have evidence that there is at least one other FMF gene on another chromosome. By two point linkage analysis, the FMF gene mapped about 20 centimorgans telomeric to the DNA marker D17S74 (pCMM86), with a lod score of 2.48 (3.0 is required for definitive proof). We have subsequently identified four other markers in this area of chromosome 17 (D17S35, D17S40, D17S46, and growth hormone) which gave similar results. Multipoint linkage analysis, using D17S74 and D17S40 as fixed markers, demonstrated a maximum lod score of 3.28 approximately 10 cM telomeric to D17S40. We also found a significant probability of genetic locus heterogeneity in the families; only 16 of the 26 families examined showed evidence of linkage to chromosome 17. When this subset of families was considered independently in the multipoint analysis, the FMF susceptibility gene mapped to the 13 centimorgan interval between D17S74 and D17S40 (lod = 9.33).